6ZXO

Crystal structure of His-tagged human thymidylate synthase (HT-hTS) in complex with FdUMP and Raltitrexed (Tomudex)

6ZXO の概要

• エントリーDOI: 10.2210/pdb6zxo/pdb
• 分子名称: Thymidylate synthase, TOMUDEX, 5-FLUORO-2'-DEOXYURIDINE-5'-MONOPHOSPHATE, ... (6 entities in total)
• 機能のキーワード: human thymidylate synthase, hts, active conformation, fdump, ratitrexed, tomudex, methyltransferase, transferase, folate pathway
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 227981.00

構造登録者

Pozzi, C.,Mangani, S. (登録日: 2020-07-30, 公開日: 2021-05-19, 最終更新日: 2024-11-20)

主引用文献

Pozzi, C.,Santucci, M.,Marverti, G.,D'Arca, D.,Tagliazucchi, L.,Ferrari, S.,Gozzi, G.,Losi, L.,Tassone, G.,Mangani, S.,Ponterini, G.,Costi, M.P.
Structural Bases for the Synergistic Inhibition of Human Thymidylate Synthase and Ovarian Cancer Cell Growth by Drug Combinations.
Cancers (Basel), 13:-, 2021

PubMed Abstract: Combining drugs represent an approach to efficiently prevent and overcome drug resistance and to reduce toxicity; yet it is a highly challenging task, particularly if combinations of inhibitors of the same enzyme target are considered. To show that crystallographic and inhibition kinetic information can provide indicators of cancer cell growth inhibition by combinations of two anti-human thymidylate synthase (hTS) drugs, we obtained the X-ray crystal structure of the hTS:raltitrexed:5-fluorodeoxyuridine monophosphate (FdUMP) complex. Its analysis showed a ternary complex with both molecules strongly bound inside the enzyme catalytic cavity. The synergistic inhibition of hTS and its mechanistic rationale were consistent with the structural analysis. When administered in combination to A2780 and A2780/CP ovarian cancer cells, the two drugs inhibited ovarian cancer cell growth additively/synergistically. Together, these results support the idea that X-ray crystallography can provide structural indicators for designing combinations of hTS (or any other target)-directed drugs to accelerate preclinical research for therapeutic application.

PubMed: 33923290
DOI: 10.3390/cancers13092061

実験手法

X-RAY DIFFRACTION (2.6 Å)